Endogenous FVIII activity and procedure-related FVIII use and bleeding: post hoc analysis of GENEr8-1

Introduction GENEr8-1 (270-301; NCT03370913) is an ongoing phase 3 trial of valoctocogene roxaparvovec gene therapy for severe hemophilia A. Primary study outcomes demonstrate that valoctocogene roxaparvovec enables endogenous factor VIII (FVIII) production, reduces bleeding episodes, and reduces FVIII concentrate use versus prior FVIII prophylaxis treatment. Here, we report the procedures performed and associated FVIII use post-gene transfer with valoctocogene roxaparvovec in participants of the 301 trial.

Method The 270-301 trial enrolled male participants ≥18 years of age with severe hemophilia A previously on FVIII prophylaxis and negative for anti-AAV5 antibodies. All participants received a single infusion of 6x1013 vg/kg of valoctocogene roxaparvovec. Endogenous FVIII activity was assessed by chromogenic substrate assay (CSA) throughout the study and the closest CSA measurement to the time of a procedure or bleeding event was identified.Invasive procedures were defined as major or minor based on commonly used criteria (Solimeno 2018). Per protocol, exogenous FVIII could be used to control bleeding perioperatively at the discretion of the investigator.

Results The intention-to-treat (ITT) population consisted of 134 participants who received valoctocogene roxaparvovec. As of the 2-year data cutoff, in 77 subjects, a total of 260 procedures were performed. Of 111 invasive procedures, 67 required no exogenous FVIII treatment. Of the 44 procedures performed with FVIII treatment, 11 were major (eg, joint debridement, arthrodesis) and 33 were minor (eg, dental extraction, biopsies).

In the ITT population, the post-infusion mean (SD) endogenous FVIII activity level at week 52 was 42.4 (45.3) IU/dL and at week 104 was 22.7 (32.8) IU/dL. For participants who received FVIII treatment for a procedure, mean (range) endogenous FVIII level for a major or minor procedure was 15.6 (<3–52.1) IU/dL or 16.2 (<3–93.2) IU/dL, respectively, and 50.5 (<3–255.7) IU/dL for participants who did not receive FVIII treatment. All 6 participants who underwent the 11 major procedures received perioperative exogenous FVIII regardless of their endogenous FVIII activity. More units of exogenous FVIII were administered for major procedures (mean [range], 255.4 [102.8–538.2] IU/kg) compared with minor procedures (67.2 [13.7–324.3] IU/kg).

Overall, 14 participants had 18 bleeding episodes related to a procedure (approximately 77% occurring within 48 hrs). FVIII treatment was used for 13 bleeds; using the closest CSA measurement to the time of the bleed, mean (range) FVIII activity for those requiring or not requiring FVIII treatment was 11.0 (<3–45.2) IU/dL and 60.4 (14.1–117.9) IU/dL, respectively.

Conclusion In GENEr8-1, post-infusion with valoctocogene roxaparvovec, most invasive procedures did not require FVIII treatment. Minor procedures where perioperative FVIII was administered were associated with lower participant endogenous FVIII activity.

Conflict of Interest

Doris V Quon reports consulting fees from Roche/Genentech, Novo Nordisk, BioMarin Pharmaceutical Inc., Bayer, Takeda Pharmaceutical Company, Octapharma, and Sanofi; has participated as a clinical trial investigator for BioMarin Pharmaceutical Inc., Bioverativ/Sanofi, Roche/Genentech, Shire/Takeda, and uniQure; and has received speaker honoraria and travel support from Roche/Genentech, Novo Nordisk, Takeda, Sanofi, and BioMarin Pharmaceutical Inc. Jiaan-Der Wang reports consulting fees from Bayer, Novo Nordisk, Alnylam, Pfizer, Chugai, and Sanofi; and serves as a clinical trial investigator for BioMarin Pharmaceutical Inc., Pfizer, Sanofi, Bayer, Novo Nordisk and Chugai. Michael Wang reports consulting fees from BioMarin Pharmaceutical Inc., Bayer, Bioverativ, CSL Behring, Novo Nordisk, Genentech, Takeda, HEMA Biologics, and uniQure; and participation as a clinical trial investigator for BioMarin Pharmaceutical Inc., Bayer, Bioverativ, CSL Behring, Novo Nordisk, Genentech, Takeda, HEMA Biologics, uniQure, Pfizer/Spark, and Octapharma. Dominic Pepperell reports consulting fees from Sanofi and a travel grant from Pfizer. Young Shil Park reports research support or participation as a principal investigator from BioMarin Pharmaceutical Inc., CSL Behring, Novo Nordisk, Sanofi, Takeda, Pfizer, and Chugai. Robert Klamroth reports consulting payments including advisory boards from Bayer, Biotest, BioMarin, Novo Nordisk, Octapharma, Pfizer, Roche/Cugai, Sanofi, Takeda/Shire, and SOBI; clinical trial investigator for Bayer, Biotest, BioMarin Pharmaceutical Inc., Novo Nordisk Pharma Ltd., Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and SOBI; and speaker honoraria and travel support from Bayer; Biotest; BioMarin Pharmaceutical Inc.; CSL Behring; Daiichi Sankyo Co., Ltd.; LEO; Novo Nordisk Pharma Ltd.; Octapharma; Pfizer; Roche/Chugai; Sanofi; Takeda/Shire; and SOBI. Gili Kenet reports research support from Alnylam, Bayer, Opko Biologics, Pfizer, Shire; and honoraria for consultancy from Alnylam, Bayer, Novo Nordisk, Pfizer, Roche, and Takeda. Johnny Mahlangu reports consulting payments from Catalyst BioSciences, CSL Behring, F. Hoffman-La Roche Ltd., Novo Nordisk, Spark Therapeutics, and Takeda; research support and/or participation as a principal investigator from BioMarin Pharmaceutical Inc., CSL Behring, Novo Nordisk, F. Hoffman-La Roche Ltd, SOBI, and uniQure. Steven W Pipe reports consulting fees from Apcintex, ASC Therapeutics, Bayer, BioMarin Pharmaceutical Inc., CSL Behring, HEMA Biologics, Freeline Therapeutics, Novo Nordisk, Pfizer, Regeneron/Intellia, Roche/Genentech, Sanofi, Spark Therapeutics, Takeda, and uniQure; and service as a clinical trial investigator for BioMarin Pharmaceutical Inc., Freeline Therapeutics, Genentech/Roche, Sanofi, Spark Therapeutics and uniQure. Tara M Robinson and Konstantia-Maria Chavele are employees and stockholders of BioMarin Pharmaceutical Inc. Teh-Liane Khoo has no conflict of interest to report.

Publication History

Article published online:
20 February 2023